CN102977092B - Fragrance alkyloyl tetrahydro-beta-carboline and the application of derivative in treatment malignant tumour thereof - Google Patents

Abstract

The invention discloses an aryl alkanoyl tetrahydro-β-carboline compound represented by structural formula (I) and related analogs or hydrates or pharmaceutically acceptable salts thereof, which contain the compound of the invention or a pharmaceutical combination thereof The medicine is used in the preparation of medicines for treating various malignant tumors, tumor metastasis and other diseases.

Description

Application of aromatic alkanoyl tetrahydro-β-carbolines and their derivatives in the treatment of malignant tumors

technical field

The present invention relates to a compound represented by the following structure (I) and related derivatives, and the use of the compound or the pharmaceutical composition containing the compound for treating various malignant tumor growth and tumor metastasis and other related diseases.

Background technique

Malignant tumor is one of the major diseases faced by human beings. With the rapid development of my country's economy, changes in lifestyles, increasing pressure on survival, aggravated population aging problems and deepening urbanization, the occurrence and development of malignant tumors have become an important obstacle to the further improvement of people's quality of life, and pose a serious threat to individuals and society. Bring heavy economic and spiritual burden. Around the world, about 6.9 million people die from malignant tumors every year, and about 8.7 million new cases occur. It is estimated that 12 million people will die of cancer by 2030. Therefore, the research and development of anti-tumor drugs has always been in a very critical position. However, most of the anti-tumor drugs currently on the market are aimed at a single drug target or have no clear target, the effect is not ideal, and long-term use can easily lead to drug resistance. Cancer patients are eager to find drugs with better anti-tumor effect, better safety and less side effects. Therefore, it is necessary to develop new anti-tumor drugs targeting new targets and multi-targets.

EGFR is a member of the epidermal growth factor receptor family, and the EGFR signaling pathway plays an important regulatory role in physiological processes such as cell growth, proliferation, differentiation, apoptosis, angiogenesis, tumor invasion and metastasis. Phosphorylation of EGFR or other results of its abnormal activity may cause tumors, diabetes, immunodeficiency and cardiovascular diseases. At present, there are many drugs targeting EGFR to treat tumors and other diseases, such as antibody drugs such as cetuximab and small molecule drugs such as tinib. The TGF-β signaling pathway plays an important role in the occurrence and development of many diseases. Its overactivation can cause malignant tumors, inflammation, and fibrosis of the liver and kidney. The TGF-β signaling pathway has become a popular target in drug development. Recent studies have shown that the TGF-β signaling pathway is also highly activated in the islets of diabetic mice, and when this pathway is inhibited, it will be beneficial to the treatment of diabetes. In the TGF-β cell signaling pathway, when the pathway is activated, it can cause the phosphorylation of smad3, and then be activated. The activated smad3 will enter the nucleus from the cytoplasm, and the phosphorylated smad3 in the nucleus can participate in the regulation of many downstream genes, so trying to inhibit the phosphorylation of smad3 may be of great significance to inhibit the TGF-β signaling pathway and treat diabetes.

β-carboline compounds are a class of compounds containing an indolopyridine structure, and they are a class of alkaloids isolated from Sapotaceae, Apocynaceae and Streptomyces. According to literature reports, natural or synthetic small molecular compounds containing β-carboline or tetrahydro-β-carboline structure have various biological activities, such as antithrombotic activity, antimalarial activity, neuroprotective effect, etc. (J. Med. Chem. 2010, 3106-16). However, compounds containing this type of structure usually have several obvious shortcomings. First, the molecular mechanism of action of the compound is not clear enough, so the research on its pharmacological effect is relatively lacking; in addition, another defect of this type of compound is that the physical and chemical properties of the compound are not enough. Ideally, this largely limits the druggability studies of such compounds. Tetrahydro-β-carboline compounds also have various physiological activities, and have more favorable physical and chemical properties than carbolines. Therefore, it is necessary to creatively carry out oriented derivatization on tetrahydro-β-carboline compounds to form a new class of tetrahydro-β-carboline compounds, increase their drug-like properties, and enable them to be used in subsequent clinical applications. ex-study. The arylalkylacyltetrahydro-β-carbolines and their derivatives proposed by the present invention fulfill this need and provide other related advantages.

Contents of the invention

The present invention obtains specific aryl alkyl acyl tetrahydro-β-carboline derivatives by introducing some chemical groups into the left half of aryl alkyl acyl tetrahydro-β-carboline, which is proved to be effective on tumor growth Both have excellent therapeutic effects on cancer and metastasis. With the help of gene expression profile chip analysis and other related experimental verifications, it is shown that such compounds are likely to be used as multi-targets (including epidermal growth factor EGFR and transforming growth factor β receptor TGFβR, etc.) antitumor drug candidates. In addition, after the introduction of some specific groups, the physical and chemical properties of the compound have changed greatly, including the water solubility and pharmacokinetic properties of the compound have been greatly improved.

The first object of the present invention is to provide a tetrahydro-β-carboline small molecular organic compound as shown in the following structural formula (I) or a hydrate or a pharmaceutically acceptable salt thereof, which has the following structural formula (I): The structure shown:

in:

m is 0-8 CH ₂ ;

n is 0-3 CH ₂ ;

It is any one of a monocyclic aromatic group, a polycyclic aromatic group, and a polycyclic aromatic group; the monocyclic aromatic group includes a phenyl group, an azaaryl group, a sulfur heteroaryl group, and an oxaaryl group; the polycyclic aromatic group An aromatic group and a polyheterocyclic aromatic group refer to a group containing two or more monocyclic aromatic groups.

R is _a substituent on the aromatic ring, including single substitution and multiple substitution, independently selected from one or more of the following groups: hydrogen, amino, cyano, hydroxyl, nitro, halogen, carboxyl, alkyl, alkane Oxygen, amino, cycloalkoxy, cycloamino, C ₂ -C ₁₂ alkenyl, C ₂ -C ₁₂ alkynyl, C ₃ -C ₁₂ cycloalkyl, benzyl, alkylcarbonyl, C ₂ - C ₁₂ alkenylcarbonyl, C ₃ -C ₁₂ cycloalkylcarbonyl, phenylcarbonyl, benzylcarbonyl, alkoxycarbonyl, ester, sulfoxide, sulfone, sulfinamide, sulfonamide; morpholinyl ; piperazinyl;

R ₂ is arbitrarily selected from one of the following groups: hydrogen, alkyl, halogen, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, aryl, heterocyclic aromatic Benzyl, phenethyl, phenylpropyl, alkoxy, alkylamino, alkylcarbonyl and arylcarbonyl, morpholinomethyl, hydroxymethyl;

R ₃ and R ₄ substituents are arbitrarily selected from one or more of the following groups: hydrogen, alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, Aryl, heteroaryl, benzyl, phenethyl, phenylpropyl, amino, cyano, nitro, halogen;

R is a substituent _on the aromatic ring, independently selected from one, two or more of the following groups: hydrogen, amino, cyano, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxy, Substituted amino, cycloalkoxy, cycloalkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, aryl, heteroaryl, benzyl , Alkylcarbonyl, C ₂ -C ₆ alkenylcarbonyl, C ₃ -C ₆ cycloalkylcarbonyl, phenylcarbonyl, benzylcarbonyl, alkoxycarbonyl, ester group, sulfoxide group, sulfone group, sulfinamide group , Sulfonamido; Morpholinyl; Piperazinyl;

The R ₆ substituent is arbitrarily selected from one of the following groups: hydrogen, alkyl, hydroxymethyl, alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkane group, C ₃ -C ₈ cycloalkenyl group, aryl group, heterocyclic aromatic group, benzyl group, phenethyl group, phenylpropyl group, alkylamino group.

In structural formula (I), when When it is a five-membered aromatic ring, it is represented by the following structural formula (II):

in:

A, B and D independently select one of nitrogen, oxygen, sulfur or CR ₅ groups; make maintain aromaticity;

The R ₇ substituent is arbitrarily selected from one of the following groups: hydrogen, alkyl, hydroxymethyl, alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkane group, C ₃ -C ₈ cycloalkenyl group, aryl group, heterocyclic aromatic group, benzyl group, phenethyl group, phenylpropyl group, alkylamino group.

In structural formula (I), when When it is a six-membered aromatic ring, it is represented by the following structural formula (III):

Wherein: E, F, G and H independently select one of nitrogen or CR ₅ groups; make Keep aromatic.

In structural formula (III), when When it is a benzene ring, it is represented by the following structural formula (IV):

in:

R ₈ , R ₉ , R ₁₀ and R ₁₁ are substituents on the benzene ring, each independently selected from one of the following groups: hydrogen, amino, cyano, hydroxyl, nitro, halogen, carboxyl, alkyl, alkane Oxygen, substituted amino, cycloalkoxy, cycloalkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, aryl, heterocyclic aryl , benzyl, alkylcarbonyl, C ₂ -C ₆ alkenylcarbonyl, C ₃ -C ₆ cycloalkylcarbonyl, phenylcarbonyl, benzylcarbonyl, alkoxycarbonyl, ester, sulfoxide, sulfone, sulfoxide Sulfonamide, sulfonamide; Morpholinyl; Piperazinyl;

In structural formula (III), when When it is a benzene ring, n is one CH ₂ , and when R ₂ , R ₃ and R ₄ are all hydrogen, it is represented by the following structural formula (V):

In structural formula (III), when When it is a benzene ring, m and n are both CH ₂ , and when R ₂ , R ₃ and R ₄ are all hydrogen, it is formed by

The following structural formula (VI) represents:

In structural formula (III), when When it is a benzene ring, the m and n parts are 1 CH ₂ , and when the R ₂ , R ₃ and R ₄ parts are hydrogen, when R ₈ ,

When any three of R ₉ , R ₁₀ and R ₁₁ are hydrogen, they are represented by the following structural formula (VII):

Wherein X is methylene; Acyl; Amino; Oxygen; Sulfur; Sulfonyl;

R ₁₂ is arbitrarily selected from one of the following groups: hydrogen, amino, cyano, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxy, substituted amino, cycloalkoxy, cycloalkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, aryl, heterocyclic aryl, benzyl, alkylcarbonyl, C ₂ -C ₆ alkenylcarbonyl, C ₃ -C ₆ cycloalkylcarbonyl, phenylcarbonyl, benzylcarbonyl, alkoxycarbonyl, ester, sulfoxide, sulfone, sulfinamide, sulfonamide; morpholinyl; piperazinyl; formyl Morpholine, Acylethylmorpholine, Acylpropylmorpholine; Piperazinyl, Acylmethylpiperazine, Acylethylmethylpiperazine, Acylpropylmethylpiperazine, Methylpiperazinyl; Amino Acid Residues (Glycine, Serine, Alanine, Threonine, Valine, Isoleucine, Leucine, Tyrosine, Phenylalanine, Histidine, Proline, Aspartic Acid, Methylthio amino acid, glutamic acid, tryptophan, lysine, cysteine, arginine, glutamine, asparagine), straight chain amino acid, branched chain amino acid, erythrose, threose, to Threose, allose, altrose, gulose, idose, talose, ribose, deoxyribose, xylose, alatose, glucose, mannose, galactose, fructose, amino sugar, oligosaccharide .

In structural formula (III), when When it is a benzene ring, m and n are both CH ₂ , when R ₂ , R ₃ and R ₄ are hydrogen, and when any three of R ₈ , R ₉ , R ₁₀ and R ₁₁ are hydrogen, It is represented by the following structural formula (VII): m, n are 1 CH ₂ , R ₂ , R ₃ and R ₄ are hydrogen, when any two of R ₈ , R ₉ , R ₁₀ and R ₁₁ are When the group is hydrogen, it is represented by the following structural formula (VIII):

Wherein X and Y are respectively methylene; acyl; amino; oxygen; sulfur; sulfonyl;

R ₁₂ and R ₁₃ are arbitrarily selected from one of the following groups: hydrogen, amino, cyano, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxy, substituted amino, cycloalkoxy, cycloalkylamine C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, aryl, heterocyclic aryl, benzyl, alkylcarbonyl, C ₂ -C ₆ alkenyl Carbonyl, C ₃ -C ₆ cycloalkylcarbonyl, phenylcarbonyl, benzylcarbonyl, alkoxycarbonyl, ester, sulfoxide, sulfone, sulfinamide, sulfonamide; morpholinyl; piperazinyl ; Formylmorpholine, acylethylmorpholine, acylpropylmorpholine; piperazinyl, acylmethylpiperazine, acylethylmethylpiperazine, acylpropylmethylpiperazine, methylpiperazinyl; Amino acid residues (glycine, serine, alanine, threonine, valine, isoleucine, leucine, tyrosine, phenylalanine, histidine, proline, aspartic acid , Methionine, Glutamic Acid, Tryptophan, Lysine, Cysteine, Arginine, Glutamine, Asparagine), Linear Amino Acids, Branched Chain Amino Acids, Erythrose, Sua Sugar, lyxose, allulose, altrose, gulose, idose, talose, ribose, deoxyribose, xylose, aramose, glucose, mannose, galactose, fructose, amino sugar , oligosaccharides.

The present invention also provides small molecule organic compounds, hydrates or pharmaceutically acceptable salts of any of the aforementioned arylalkanoyltetrahydro-β-carbolines or derivatives thereof. Wherein said acceptable salts include acid salts and alkali salts, groups suitable for contacting human or animal tissues without undue toxicity or carcinogenicity, with particular preference for those groups without irritation, allergic reaction or other complications . Included are basic or organic salts of acidic residues such as carboxylic acids, as well as inorganic and organic acidic salts of basic residues such as amines. Anions that can be used for salt formation include, but are not limited to: hydrochloride, hydrobromide, sulfate, phosphate, acetate, tartrate, salicylate, citrate, methanesulfonate, p-toluenesulfonate, lactate, acetone Acid, Maleate, Succinate, Ascorbate, Benzoate, Bicarbonate, EDTA, Formate, Glutamate, Glycolate, Hydroxymaleate, Malate, Mandelate, Sulfamate Acid, sulfonate, chloride, bromide, etc. Similarly, cations that can be used for salt formation include, but are not limited to, ammonium, ethylenediamine, choline, diethanolamine, procaine, and metals such as sodium, potassium, magnesium, aluminum, zinc, and lithium.

In some aspects of the present invention, detection labels such as radioactivity, fluorescent groups or biotin can be used to label the aryl alkanoyl tetrahydro-β-carboline compounds and related derivatives provided by the present invention.

In the present invention, aryl alkanoyl tetrahydro-β-carboline small molecule organic compounds or their hydrates or pharmaceutically acceptable salts include but are not limited to the following compounds:

N-Phenylacetyl-(6-trifluoromethyl)-1,3,4,9-tetrahydro-1H-β-carboline

N-Phenylacetyl-(6-trifluoromethoxy)-1,3,4,9-tetrahydro-1H-β-carboline

6-(2-morpholinoethyl)aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(4-methylpiperazine)carbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(2-(Dimethylamino)ethyl)aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(3-(Dimethylamino)propyl)aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(4-Morpholinylphenyl)aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(4-Dimethylaminophenyl)aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(4-Aminosulfonyl)aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(N,N-bis(2-hydroxyethyl))aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(2-(2-Hydroxyethoxy)ethyl)aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(Serine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(Aspartic acid carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(alaninecarbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(Phenylalaninecarbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(Glutamic acid carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(Prolinecarbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(Glycinecarbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(Tyrosinecarbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(Histidinecarbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-cyano-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-Nitro-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-Benzyloxy-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-Methoxycarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-Amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-Hydroxy-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-Carboxy-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-Methyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

5-Amino-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline

7-Amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

5-(2-(N-morpholinyl))acetylamino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

5-(2-(4-methylpiperazinyl))acetylamino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline 5-(2-amino)acetyl Amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

5-(2-threonyl)amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

5-(2-Prolinyl)amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

9-(4-Bromobenzyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

9-Methyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

8-Fluoro-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(2-Amino)acetylamino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

N-Phenylacetyl-6,8-difluoro-1,3,4,9-tetrahydro-1H-β-carboline

N-phenylacetyl-6,8-difluoro-9-p-bromobenzyl-1,3,4,9-tetrahydro-1H-β-carboline

9-Benzyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

9-(4-fluorobenzyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

9-(4-methylcarboxylate benzyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

9-(4-Carboxybenzyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

9-(Methoxycarbonylmethyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

9-(Carbonylmethyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

9-(4-(morpholinyl)carbonylmethyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

5-Methoxycarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

5-(Valine amino)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

5-(Alanineamino)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

5-(3-Amino)propionylamino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline.

The present invention provides a pharmaceutical composition, which contains one or more aryl alkanoyl tetrahydro-β-carboline small molecule organic compounds, hydrates or pharmaceutically acceptable salts described in the present invention, and pharmaceutical acceptable carrier.

Wherein, in a specific embodiment, the composition is formulated as an injectable fluid, aerosol, cream, gel, pill, capsule, syrup, transdermal patch or excipient.

The present invention provides prodrugs of aryl alkanoyl tetrahydro-β-carboline small molecule organic compounds and related derivatives described in formula (I). "Prodrug" means that the compound itself may not fully meet the structural requirements of the compounds provided herein but undergoes in vivo changes to produce the compounds of the formulas provided herein after administration to a patient. Examples of prodrugs include, but are not limited to, esters, eg, that can be modified by the presence of functional groups such that the modification is cleaved in vivo to yield the parent compound.

The compounds of the present invention also include dimeric and multimeric compounds in which the compounds represented by formula (I) are linked in various ways.

The invention provides the use of aryl alkanoyl tetrahydro-β-carboline small molecular organic compounds and related derivatives, hydrates or pharmaceutically acceptable salts in inhibiting tumor growth and metastasis.

In one embodiment, the tumor cells include but not limited to head and neck cancer cells, thyroid cancer cells, esophageal cancer cells, nasopharyngeal cancer cells, liver cancer cells, lung cancer cells, prostate cancer cells, skin cancer cells, bone cancer cells, cervical cancer cells, Cancer cells, intestinal cancer cells, pancreatic cancer cells, breast cancer cells, leukemia cells, ovarian cancer cells, gastric cancer cells, bladder cancer cells, kidney cancer cells, skin cancer cells, oral cancer cells, malignant lymphoma cells, etc.

The present invention also provides the application of aryl alkanoyl tetrahydro-β-carboline compounds and related derivatives in the preparation of medicines for treating malignant tumors; wherein, the malignant tumors include head and neck cancer, thyroid cancer, esophageal cancer, nasal Pharyngeal cancer, liver cancer, lung cancer, prostate cancer, skin cancer, bone cancer, cervical cancer, bowel cancer, pancreatic cancer, breast cancer, leukemia, ovarian cancer, stomach cancer, bladder cancer, kidney cancer, skin cancer, oral cancer, malignant lymphoma .

The present invention also provides the application of aryl alkanoyl tetrahydro-β-carboline compounds and related derivatives or their hydrates or pharmaceutically acceptable salts in the preparation of drugs for the treatment of malignant tumor metastasis and recurrence; wherein, the The above malignant tumors include head and neck cancer, thyroid cancer, esophageal cancer, nasopharyngeal cancer, liver cancer, lung cancer, prostate cancer, skin cancer, bone cancer, cervical cancer, bowel cancer, pancreatic cancer, breast cancer, leukemia, ovarian cancer, stomach cancer, bladder cancer cancer, kidney cancer, skin cancer, oral cancer, malignant lymphoma.

The present invention also provides the application of aryl alkanoyl tetrahydro-β-carboline compounds and related derivatives or their hydrates or pharmaceutically acceptable salts in the preparation of anti-tumor therapeutic drugs, and the drugs are used to induce the acquisition of Sexual drug resistance leads to anticancer therapy after chemotherapy failure.

The present invention also provides the use of aryl alkanoyl tetrahydro-β-carboline compounds and related derivatives or hydrates or pharmaceutically acceptable salts thereof in the preparation of medicines for treating osteolytic bone injuries.

The present invention also provides the application of aryl alkanoyl tetrahydro-β-carboline small molecule organic compound or its hydrate or pharmaceutically acceptable salt in the preparation of medicine for treating lung failure caused by tumor.

The medicine of the present invention is used alone or in combination with other medicines.

Description of drawings

Figure 1 shows the results of the inhibitory rate (%) of the compound of the present invention on the proliferation of human prostate cancer cell PC-3 at a concentration of 10 micromole/liter.

Figure 2 shows the results of the inhibitory rate (%) of the compound of the present invention on the proliferation of human lung cancer cell H1299 at different concentrations.

Figure 3 shows the results of the inhibitory rate (%) of the compounds of the present invention on the migration of human prostate cancer cell PC-3 at a concentration of 10 micromole/liter.

Fig. 4 is a graph showing the effect of the compounds of the present invention on the clone-forming ability of human lung cancer cell A549, in which the drug concentrations of the four culture dishes from left to right are 0, 1, 5, and 10 μmol/L, respectively.

Fig. 5 is a graph showing the inhibitory effect of the compounds of the present invention on the growth of lung cancer in nude mice. Among them, Figure 5A is a photo of the therapeutic effect on non-small cell lung cancer in mice after the 7th, 14th, 21st and 28th day of administration taken by the animal in vivo imaging system. The shaded part in the figure represents the fluorescent signal, indicating that there are tumor cells in this area Aggregation, and the degree of cell aggregation deepened from the outside to the inside; Figure 5B is a graph showing the relationship between tumor volume and the number of days of administration, and Figure 5C is the change in tumor weight of the mice in the administration group and the control group.

Fig. 6 is a graph showing the effect of the compound of the present invention on the inhibition of lung metastasis of breast cancer and the effect on the survival rate of mice. Among them, Figure 6A is a photo of the therapeutic effect of different doses of the compound of the present invention on the lung metastasis of breast cancer in mice after administration on the 7th, 14th and 21st day taken by the animal in vivo imaging system, and the shadow in the figure represents the fluorescent signal, indicating that There are tumor cell accumulations in this area, and the degree of cell aggregation deepens from the outside to the inside; Figure 6B is the calculation of the amount of lung metastasis of breast cancer in mice through the animal in vivo imaging system, and Figure 6C is the survival rate of mice in the overall animal experimental model after 20 days of administration The change.

detailed description

The present invention will be described in further detail in conjunction with the following specific examples and accompanying drawings, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, changes and advantages conceivable by those skilled in the art are all included in the present invention, and the appended claims are the protection scope.

¹ H-NMR was measured by Bruker300 or Bruker400; MS was measured by VGZAB-HS or VG-7070, and all were ESI methods unless otherwise noted; all solvents were re-distilled before use, and the anhydrous solvents used were All were obtained by drying according to the standard method; except for the instructions, all the reactions were carried out under the protection of argon and tracked by TLC, and the post-treatment was washed with saturated brine and dried with anhydrous magnesium sulfate; the purification of the products was carried out except for the instructions. Column chromatography using silica gel (200-300 mesh); the silica gel used, including 200-300 mesh and GF ₂₅₄ , are produced by Qingdao Ocean Chemical Factory or Yantai Yuanbo Silica Gel Company.

Embodiment one: the preparation of each compound

Example 1-1, Synthesis of N-phenylacetyl-(6-trifluoromethyl)-1,3,4,9-tetrahydro-1H-β-carboline (NTC001)

Take 4-trifluoromethylphenylhydrazine hydrochloride (425mg, 2mmol) in 14mL alcohol and water (volume ratio is 5/1), slowly add 4-chlorobutyraldehyde dimethyl acetal (367mg, 2.2 mmol), then warming and flowing for 5-18 hours. Complete, remove most of the solvent under reduced pressure, then adjust the pH value of the solution to 12, extract three times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, and distill off the solvent under reduced pressure to obtain the intermediate 5-trifluoroform Tritryptamine (crude product 464 mg).

5-Trifluoromethyltryptamine (464mg, 2.0mmol) was dissolved in 3mL of glacial acetic acid, and 37% formaldehyde solution (45μL, 0.60mmol) was added dropwise under the protection of nitrogen to complete the addition and react overnight. Most of the acetic acid was evaporated under reduced pressure, the pH value of the solution was adjusted to 12, extracted with ethyl acetate, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the intermediate 6-trifluoromethyl-1 was obtained after purification by column chromatography. 3,4,9-Tetrahydro-1H-β-carboline (150 mg, 31% yield).

Dissolve phenylacetic acid (57mg, 0.42mmol) in dry DMF (1mL), add EDC (105mg, 0.55mmol) and HOBt (62mg, 0.46mmol) at 0°C, stir in ice bath for 10 minutes, add compound 6-3 Fluoromethyl-1,3,4,9-tetrahydro-1H-β-carboline (63 mg, 0.32 mmol). After completion, remove the ice bath, react at room temperature for 3 hours, and purify by column chromatography after routine treatment to obtain N-phenylacetyl-(6-trifluoromethyl)-1,3,4,9-tetrahydro-1H-β-carba morphine (62 mg, 66% yield). ¹ HNMR (300MHz, DMSO-d ₆ ): ¹ HNMR (300MHz, DMSO-d6): δ11.37(brs, 1H), 7.77(d, J=9.3Hz, 1H), 7.49(d, J=8.4Hz , 1H), 7.32-7.24(m, 6H), 4.74(s, 2H), 3.87-3.84(m, 4H), 2.73-2.66(m, 2H).

Preparation of NTC002-52 carboline compounds shown in Example 2-52 and Table 1 (see reference below for specific process)

Example 2: The compound of the present invention has the inhibitory effect on the proliferation and migration of human lung cancer cells, prostate cancer cells, breast cancer cells and colon cancer cells, and the inhibitory effect on the ability of tumor cell clone formation at a certain dose

(1) Cell culture

Cells used in this experiment such as head and neck cancer cells, thyroid cancer cells, esophageal cancer cells, nasopharyngeal cancer cells, liver cancer cells, lung cancer cells, prostate cancer cells, skin cancer cells, bone cancer cells, cervical cancer cells, intestinal cancer cells, pancreatic cancer cells Cancer cells, breast cancer cells, leukemia cells, ovarian cancer cells, gastric cancer cells, bladder cancer cells, kidney cancer cells, skin cancer cells, oral cancer cells, malignant lymphoma cells, etc. were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences and adhered to culture in In a constant temperature incubator at 37°C (humidity 95%, CO ₂ 5%), the culture medium is DMEM high glucose medium (Gibco) containing 10% fetal bovine serum (Front).

(2), SRB (sulfonyl rhodamine) assay for cell proliferation

(1) PC-3 cells were seeded into 96-well culture plates at a density of 5×10 ³ /well, and cultured overnight.

(2) Compounds with different concentrations were added sequentially, so that the final concentrations were 1 μM, 2.5 μM, 5 μM, 10 μM, 25 μM, and 50 μM, and the same amount of DMSO was added to the control group (6 replicate wells for each group), and the culture was continued for 24 hours.

(3) Add cold TCA (trichloroacetic acid, 10%, w/V) to each well for fixation, and incubate at 4°C for 30 min.

(4) Rinse with running water 5 times and air dry.

(5) Add 50 μL SRB staining solution (4%, w/V) to each well and incubate at room temperature for 10 min for staining.

(6) Aspirate the dye solution, add 100 μL of 1% acetic acid to each well and wash 5 times to remove unbound dye.

(7) After air-drying, add 100 μL of 100 mM Tris solution to each well, and shake to dissolve the bound SRB dye. The 96-well plate was placed in a microplate reader (SPECTRAMAX190), and the OD value was measured at 515nm. Statistical analysis of drug effects on cell proliferation levels. The results are shown in Figure 1, wherein: the compound of the present invention has a very obvious inhibitory effect on the proliferation of human prostate cell H1299 at 10.0 μmol/L, as shown in Figure 1 . Most of the compounds have inhibitory effects on the proliferation of prostate cancer cells. Among some of the listed compounds, NTC001, NTC002, NTC005, NTC007, NTC008, NTC011, NTC015, NTC021, NTC026, NTC028, NTC033, NTC036, NTC038, NTC042, NTC045, Compounds such as NTC049 and NTC052 can inhibit the proliferation of prostate cancer cell PC-3 by 60% at a concentration of 10.0 μmol/L

above.

The compound of the present invention also has a significant inhibitory effect on human lung cancer cells, as shown in FIG. 2 . From similar experiments, it can be found that the compound of the present invention also has a very significant inhibitory effect on the proliferation of human non-small cell lung cancer cell H1299. Significantly.

In addition, the compound of the present invention is effective against head and neck cancer cells, thyroid cancer cells, esophageal cancer cells, nasopharyngeal cancer cells, liver cancer cells, lung cancer cells, skin cancer cells, bone cancer cells, cervical cancer cells, intestinal cancer cells, pancreatic cancer cells, The inhibition of the proliferation activity of breast cancer cells, leukemia cells, ovarian cancer cells, gastric cancer cells, bladder cancer cells, kidney cancer cells, skin cancer cells, oral cancer cells, and malignant lymphoma cells also has similar implementation effects.

(3) Inhibitory effect of the compound of the present invention on tumor cell migration.

When cells are cultured in vitro, they will move along the culture plane to the part with fewer cells. Taking advantage of this phenomenon, a "scar" is artificially "marked" in the culture well that is already full of cells, and the cells on both sides of the "scar" will move to the "scar" area, and finally refill the area, which is the so-called "scar" area. scar healing effect. According to the number of cells that move to the "scar" area and the degree of "scar healing", the movement ability of the cells can be judged.

Prostate cancer cell PC-3 was inoculated into a 12-well plate, and the cells were cultured in a 5% CO ₂ incubator at 37°C for 24 hours until the cells grew to 100% full. The serum-free medium was replaced, and the culture was continued for 12 h. In the culture well full of cells, use 10 μl sterile tip to scratch longitudinally along the diameter of the culture well, wash the cells twice with PBS after scratching, wash away the floating cells, add 1.0ml complete medium to each well . Drugs of different concentrations were added to the cell culture wells, and the culture plate was placed in a CO ₂ incubator, and conventional culture was continued at 37°C for 24 hours. Observe the movement of the part of the cell that wants to be marked under a microscope, and take pictures. Statistically analyze the number of cells migrating into the streaked area in different doses of drug groups to determine the effect of drugs on cell migration.

Part of the experimental results are shown in Figure 3. Figure 3A is a diagram of tumor cell migration effects, and Figure 3B is a statistics of migration effects. Among the four compounds tested in the cell scratch migration experimental model of prostate cancer cell PC-3, compounds NTC028, NTC038 can significantly inhibit PC-3 migration at a concentration of 10 μM, indicating that this type of compound significantly inhibits the migration of tumor cells in this migration model.

In addition, the compound of the present invention is effective against head and neck cancer cells, thyroid cancer cells, esophageal cancer cells, nasopharyngeal cancer cells, liver cancer cells, lung cancer cells, skin cancer cells, bone cancer cells, cervical cancer cells, intestinal cancer cells, pancreatic cancer cells, Inhibition of the migration activity of breast cancer cells, leukemia cells, ovarian cancer cells, gastric cancer cells, bladder cancer cells, kidney cancer cells, skin cancer cells, oral cancer cells, and malignant lymphoma cells also has similar implementation effects.

(4), colony formation method (colony formation): detecting the proliferation and tumorigenic ability of tumor cell clones formed in vitro

Tumor cells can divide and proliferate in vivo to finally form solid tumors visible to the naked eye. In vitro experimental models, the ability of tumor cells to form solid tumors in vivo can be reflected by the strength of their clone-forming ability.

Inoculate the tumor cells in a 35mm culture dish at a density ^of 1x10 cells/dish, group them after 24 hours of culture, and add different concentrations of the compound to be tested, so that the final concentrations are 1.0 μmol/L, 5.0 μmol/L, and 10.0 μmol /L, the control group was added an equal amount of DMSO. The culture was continued, and the medium and the corresponding concentration of compounds were replaced every 3 days. After 21 days, the medium was discarded, washed three times with PBS, fixed with 4% paraformaldehyde at room temperature for 10 minutes, stained with 1% crystal violet for 10 minutes, and washed with tap water. Photographs were taken under a microscope, and the number of cell clones formed was counted. The experimental results are shown in Figure 4. Among them, compounds NTC003, NTC015, NTC023, NTC029, NTC035 and NTC047 have obvious inhibitory effect on the colony formation ability of non-small cell lung cancer cells (such as A549 cells). The cloning ability of this strain of lung cancer cells was inhibited by about 20%, and the clone formation of the lung cancer cells was basically inhibited at a concentration of 5.0 μmol/L, and the clone formation of the lung cancer cells was completely inhibited at a concentration of 10.0 μmol/L. From one point of view, this kind of compound has a strong effect of inhibiting tumor growth.

Embodiment 3: The therapeutic effect of the compound of the present invention on non-small cell lung cancer

This experiment simulated the onset and treatment process of clinical non-small cell lung cancer growth and metastasis. 4-6 weeks old nude mice, orthotopically inject 5×104 mouse non-small cell lung cancer cells PC-9 in the lungs. After 7 days of tumor-bearing, the mice were randomly divided into 4 groups on average, which were the control group, the 1.0mg/kg/day dose administration group, the 2.5mg/kg/day dose administration group and the 5.0mg/kg/day dose administration group. medicine group. The administration group was injected intraperitoneally with corresponding doses of drugs, and the control group was injected with the same amount of solvent (DMSO). The administration was continued until 21 days, and the in vivo imaging technique (IVIS) was used to observe the metastasis of tumor cells to the lungs of mice.

The results are shown in Figure 5, and Figure 5 is the therapeutic effect on non-small cell lung cancer in mice after 21 days of medication (the 28th day) (pictures were taken by an animal live imaging system, since the tumor cells contain fluorescence, fluorescence can be used to To determine the location and number of tumor cells, the darker the shadow color, the stronger the fluorescent signal, indicating that there are tumor cell accumulations in this area, and the degree of cell aggregation deepens from the outside to the inside. The results are shown in Figure 5A and 5B, shown at 1.0mg/kg Compounds NTC002, NTC008, NTC015, NTC023, NTC032, NTC035 and NTC039 at a dose of 2.5mg/kg/day can significantly inhibit the growth of lung cancer, and 5.0mg/kg/day of the compound Then the growth of lung cancer was basically inhibited. From Figure 5C, it can be found that there is no significant difference in the body weight of the four groups of mice, which shows from another aspect that these mice have strong tolerance to this type of compound, and the compound is less toxic.

Embodiment 4: The therapeutic effect of the compound of the present invention on the lung metastasis of breast cancer in the tail vein injection model of nude mice

Inject 5×10 ⁴ breast cancer cells MDA-MB-231 into the left ventricle of female Balb/c mice at the age of 4-6 weeks, and divide them into three groups according to the weight of the mice, which are respectively the control group and 1.0mg /kg/day dose administration group and 5.0mg/kg/day dose administration group. The number of metastases of breast cancer cells was regularly observed and calculated by the animal in vivo fluorescence imaging system (IVIS), so as to clarify the effect of the compound on the process of lung metastasis of breast cancer and calculate the survival rate of mice. The result is shown in Figure 6, where:

(1) Figure 6A shows the treatment effect of the mouse breast cancer lung metastasis model after 20 days of medication (pictures are taken by an animal live imaging system, since the tumor cells contain fluorescence, the location and number of tumor cells can be determined by fluorescence, The shadow in the figure represents the accumulation of tumor cells in this area, and the shade of the shade represents the amount of tumor cell accumulation, and the degree of cell accumulation deepens from the outside to the inside. Since this breast cancer model often metastasizes to the lungs, it can be seen that the mice in the control group There are a large number of tumor cell metastases in the lungs. However, at the dose of 1.0 mg/kg/day of the compounds (NTC001, NTC005, NTC008, NTC015, NTC023, NTC032, NTC037, NTC043 and NTC049), there are only a small amount of tumor cell accumulation in the lungs, However, at a dose of 5.0 mg/kg/day, the imaging of tumor cells metastasizing to the lungs was almost invisible.

(2) Figure 6B shows the statistical graph of the results in Figure 6A. Compared with the control group, the distribution of metastatic lesions in mice was reduced by more than 60% and 90% respectively, as shown in the figure, illustrating that this type of compound has the effect on breast cancer Lung metastasis has obvious inhibitory effect.

(3) It can be seen from Figure 6C that after administration of different groups of mice for 20 days, the mice in the control group basically could not survive, while the administration groups (compounds NTC001, NTC005, NTC008, NTC015, NTC023, NTC032, NTC037, NTC043 and NTC049 ) mice at the dosage of 1mg/kg/day and 5mg/kg/day, the survival rate of the mice was increased to 50% and 80% respectively. It is obvious that the compound has a very significant effect on improving the survival rate of the mice.

Reference Examples 2-52

Example 1-2, Synthesis of N-phenylacetyl-(6-trifluoromethoxy)-1,3,4,9-tetrahydro-1H-β-carboline (NTC002)

Using a method similar to the preparation of compound NTC001, 4-trifluoromethylphenylhydrazine was replaced by 4-trifluoromethoxyphenylhydrazine, and finally compound NTC002 was obtained after purification by column chromatography, with a yield of 16%: ¹ HNMR (300MHz , DMSO-d ₆ ): δ11.17 (brs, 1H), 7.39-7.32 (m, 3H), 7.29-7.24 (m, 4H), 7.00 (d, J=8.4Hz, 1H), 4.72 (s, 2H), 3.86-3.82(m, 4H), 2.88-2.61(m, 2H).

Example 1-3, 6-(2-morpholine ethyl) aminocarbonyl-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline (NTC003) synthesis

Using a method similar to the preparation of compound NTC001, 4-trifluoromethylphenylhydrazine was replaced by 4-hydrazinobenzoic acid methyl ester to obtain intermediate 6-(methoxycarbonyl)-N-phenylacetyl-1,3 , 4,9-tetrahydro-1H-β-carboline, followed by alkaline hydrolysis, coupled with 2-morpholine ethylamine, and finally purified by column chromatography to obtain compound NTC003, yield %: 78%. ¹ HNMR (300MHz, DMSO-d ₆ ): δ11.12 (brs, 1H), 8.24-8.22 (m, 1H), 7.95 (d, J=16.2Hz, 1H), 7.59-7.56 (m, 1H), 7.33-7.24(m, 6H), 4.71(s, 2H), 3.87-3.82(m, 4H), 3.57(t, J=4.5Hz, 4H), 3.42-3.33(m, 2H), 2.73-2.72( m, 2H), 2.51-2.50 (m, 2H), 2.44-2.43 (m, 4H).

Example 1-4, 6-(4-methylpiperazine) carbonyl-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline (NTC004) synthesis

Using a method similar to the preparation of compound NTC003, 2-morpholinoethylamine was replaced by 4-methylpiperazine, and finally compound NTC004 was obtained after purification by column chromatography, with a yield of 81%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ11.11 (brs, 1H), 7.45-7.42 (m, 1H), 7.34-7.23 (m, 6H), 7.10-7.05 (m, 1H), 4.71 (s, 2H), 3.86-3.82 ( m, 4H), 3.51-3.45 (m, 4H), 2.71-2.61 (m, 2H), 2.31-2.30 (m, 4H), 2.19 (s, 3H).

Example 1-5, 6-(2-(dimethylamino)ethyl)aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC005) Synthesis

Using a method similar to the preparation of compound NTC003, 2-morpholine ethylamine was replaced by 2-(dimethylamino)ethylamine, and finally purified by column chromatography to obtain compound NTC005, yield: 87%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ11.12(brs, 1H), 8.21(s, 1H), 7.99-7.94(m, 1H), 7.58(d, J=8.1Hz, 1H), 7.33-7.24( m, 6H), 4.72 (s, 2H), 3.87-3.85 (m, 4H), 2.73-2.62 (m, 2H), 2.50-2.45 (m, 4H), 2.21 (s, 6H).

Example 1-6, 6-(3-(dimethylamino)propyl)aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC006) Synthesis

Using a method similar to the preparation of compound NTC005, 2-(dimethylamino)ethylamine was replaced by 3-(dimethylamino)propylamine, and finally purified by column chromatography to obtain compound NTC006, yield: 84 %: ¹ HNMR (300MHz, DMSO-d ₆ ): δ11.12 (brs, 1H), 8.36 (s, 1H), 7.97-7.92 (m, 1H), 7.58 (d, J=8.4Hz, 1H), 7.33-7.24(m, 6H), 4.72(s, 2H), 3.87-3.85(m, 4H), 3.29(t, J=6.3Hz, 2H), 2.72-2.61(m, 2H), 2.27(t, J=6.9Hz, 2H), 2.14(s, 6H), 1.68-1.64(m, 2H).

Example 1-7, 6-(4-morpholinylphenyl)aminocarbonyl-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline (NTC007) synthesis

Using a method similar to the preparation of compound NTC003, 2-morpholinoethylamine was replaced by 4-morpholinoaniline, and finally compound NTC007 was obtained after column chromatography purification, yield: 65%: ¹ HNMR (300MHz, DMSO- d ₆ ): δ11.18(brs, 1H), 9.90(brs, 1H), 8.13-8.07(m, 1H), 7.71-7.63(m, 3H), 7.40-7.25(m, 6H), 6.93(d , J=8.1Hz, 2H), 4.74(s, 2H), 3.88-3.86(m, 4H), 3.74(s, 4H), 3.07(s, 4H), 2.77-2.66(m, 2H).

Example 1-8, 6-(4-dimethylaminophenyl) aminocarbonyl-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline (NTC007) synthesis

Using a method similar to the preparation of compound NTC003, 2-morpholinoethylamine was replaced by 4-dimethylaminoaniline, and finally compound NTC008 was obtained after column chromatography purification, yield: 63%: ¹ HNMR (300MHz, DMSO- d ₆ ): δ11.16(brs, 1H), 9.82(brs, 1H), 8.13-8.08(m, 1H), 7.70(d, J=8.4Hz, 1H), 7.58(d, J=7.5Hz, 2H), 7.39-7.25(m, 6H), 6.72(d, J=9.0Hz, 2H), 4.74(s, 2H), 3.88-3.86(m, 4H), 2.86(s, 6H), 2.76-2.65 (m, 2H).

Example 1-9, 6-(4-aminosulfonyl)aminocarbonyl-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline (NTC007) synthesis

Using a method similar to the preparation of compound NTC003, 2-morpholine ethylamine was replaced by sulfonamide, and finally purified by column chromatography to obtain compound NTC009, yield: 63%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ13 .63(brs, 1H), 12.38(brs, 1H), 8.20-7.93(m, 2H), 7.74-7.67(m, 2H), 7.61-7.52(m, 1H), 7.44-7.24(m, 7H) , 4.72 (s, 2H), 3.88-3.86 (m, 4H), 2.73-2.65 (m, 2H).

Embodiment 1-10, 6-(N, N-bis(2-hydroxyethyl)) aminocarbonyl-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline ( Synthesis of NTC010)

Using a method similar to the preparation of compound NTC003, 2-morpholine ethylamine was replaced by diethanolamine, and finally purified by column chromatography to obtain compound NTC010, yield: 60%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ11.04 (brs, 1H), 7.46-7.42 (m, 1H), 7.32-7.24 (m, 6H), 7.08 (d, J=7.8Hz, 1H), 4.71 (s, 4H), 3.86-3.84 ( m, 4H), 3.50-3.45 (m, 8H), 2.68-2.61 (m, 2H).

Embodiment 1-11, 6-(2-(2-hydroxyethoxy) ethyl) aminocarbonyl-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline ( Synthesis of NTC011)

Using a method similar to the preparation of compound NTC003, 2-morpholinoethylamine was replaced by 2-(2-aminoethoxy)ethanol, and finally purified by column chromatography to obtain compound NTC011 with a yield of 63%: ¹ HNMR ( 300MHz, DMSO-d ₆ ): δ11.11(brs, 1H), 8.30(brs, 1H), 7.80-7.95(m, 1H), 7.69-7.58(m, 1H), 7.33-7.23(m, 6H) , 4.72(s, 2H), 4.60(s, 1H), 3.87(s, 4H), 3.54-3.52(m, 4H), 3.46-3.45(m, 4H), 2.72-2.62(m, 2H).

Example 1-12, 6-(serine carbonyl)-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline (NTC012) synthesis

Using a method similar to the preparation of compound NTC003, 2-morpholineethylamine was replaced by L-serine, and finally purified by column chromatography to obtain compound NTC012, yield: 45%: ¹ HNMR (300MHz, DMSO-d ₆ ) : δ12.55(brs, 1H), 11.15(brs, 1H), 8.17(d, J=5.7Hz, 1H), 8.06-8.01(m, 1H), 7.63(d, J=7.5Hz, 1H), 7.36-7.24 (m, 5H), 4.72 (s, 2H), 4.49 (s, 1H), 3.87 (s, 4H), 3.81 (s, 2H), 2.74-2.63 (m, 2H).

Example 1-13, 6-(aspartic acid carbonyl)-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline (NTC013) synthesis

Using a method similar to the preparation of compound NTC003, 2-morpholine ethylamine was replaced by L-aspartic acid, and finally purified by column chromatography to obtain compound NTC013, yield: 41%: ¹ HNMR (300MHz, DMSO- d ₆ ): δ12.57(brs, 2H), 11.15(brs, 1H), 8.53(d, J=5.7Hz, 1H), 8.02-7.97(m, 1H), 7.60(d, J=7.8Hz, 1H), 7.35-7.24(m, 5H), 4.79-4.72(m, 3H), 3.87(s, 4H), 2.89-2.82(m, 1H), 2.75-2.63(m, 3H).

Synthesis of Example 1-14, 6-(alanine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC014)

Using a method similar to the preparation of compound NTC003, 2-morpholine ethylamine was replaced by L-alanine, and finally purified by column chromatography to obtain compound NTC014 with a yield of 57%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ11.15(s, 1H), 8.34(d, J=5.1Hz, 1H), 8.05-7.99(m, 1H), 7.62(d, J=8.1Hz, 1H), 7.35-7.24(m, 5H), 4.72(s, 2H), 4.38(t, J=6.6Hz, 1H), 3.87(s, 4H), 2.74-2.63(m, 2H), 1.39(d, J=6.6Hz, 3H).

Synthesis of Example 1-15, 6-(phenylalanine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC015)

Using a method similar to the preparation of compound NTC003, 2-morpholine ethylamine was replaced by L-phenylalanine, and finally purified by column chromatography to obtain compound NTC015 with a yield of 49%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ11.15(s, 1H), 8.28(d, J=6.0Hz, 1H), 7.96-7.90(m, 1H), 7.53(d, J=7.8Hz, 1H), 7.29-7.14(m , 10H), 4.71(s, 2H), 4.58(s, 1H), 3.86(s, 4H), 3.23-3.18(m, 1H), 3.14-3.06(m, 1H), 2.72-2.61(m, 2H ).

Synthesis of Example 1-16, 6-(glutamic acid carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC016)

Using a method similar to the preparation of compound NTC003, 2-morpholine ethylamine was replaced by L-glutamic acid, and finally purified by column chromatography to obtain compound NTC016 with a yield of 25%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ12.44 (brs, 2H), 11.16 (s, 1H), 8.41 (s, 1H), 8.07-8.01 (m, 1H), 7.63 (d, J=8.1Hz, 1H), 7.35-7.24 ( m, 5H), 4.72(s, 2H), 4.42(s, 1H), 3.87(s, 4H), 2.74-2.63(m, 2H), 2.36-2.29(m, 2H), 1.23-1.15(m, 2H).

Example 1-17, Synthesis of 6-(proline carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC017)

Using a method similar to the preparation of compound NTC003, 2-morpholine ethylamine was replaced by L-proline, and finally purified by column chromatography to obtain compound NTC017 with a yield of 64%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ12.53(brs, 1H), 11.14(s, 1H), 7.63-7.58(m, 1H), 7.29-7.24(m, 7H), 4.72(s, 2H), 4.41(s, 1H), 3.86(s, 4H), 3.56(s, 2H), 2.71-2.63(m, 2H), 2.25(s, 1H), 1.87(s, 3H).

Synthesis of Example 1-18, 6-(glycine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC018)

Using a method similar to the preparation of compound NTC003, 2-morpholineethylamine was replaced by glycine, and finally purified by column chromatography to obtain compound NTC018 with a yield of 62%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ12. 48(brs, 1H), 11.15(s, 1H), 8.62(s, 1H), 8.03-7.98(m, 1H), 7.61(d, J=8.7Hz, 1H), 7.36-7.24(m, 5H) , 4.72 (s, 2H), 3.92 (s, 2H), 3.87-3.85 (m, 4H), 2.73-2.63 (m, 2H).

Example 1-19, Synthesis of 6-(tyrosine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC019)

Using a method similar to the preparation of compound NTC003, 2-morpholinoethylamine was replaced by tyrosine, and finally compound NTC019 was obtained after purification by column chromatography, with a yield of 29%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ12.52(brs, 1H), 11.14(s, 1H), 9.17(brs, 1H), 8.39(d, J=8.1Hz, 1H), 7.98-7.94(m, 1H), 7.55(d, J= 8.4Hz, 1H), 7.33-7.09(m, 6H), 7.10(d, J=8.4Hz, 2H), 6.63(d, J=8.4Hz, 2H), 4.72(s, 2H), 4.54(s, 1H), 3.87-3.85 (m, 4H), 3.09-2.97 (m, 2H), 2.73-2.63 (m, 2H).

Synthesis of Example 1-20, 6-(histidine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC020)

Using a method similar to the preparation of compound NTC003, 2-morpholinoethylamine was replaced by tyrosine, and finally purified by column chromatography to obtain compound NTC020 with a yield of 50%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ11.57(s, 1H), 11.36(s, 1H), 8.27(s, 1H), 7.99-7.93(m, 1H), 7.62-7.54(m, 2H), 7.37-7.18(m, 6H), 6.81 (s, 1H), 4.71 (s, 2H), 4.51-4.47 (m, 1H), 3.87-3.84 (m, 4H), 3.15-3.06 (m, 2H), 2.72-2.62 (m, 2H).

Synthesis of Example 1-21, 6-cyano-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC021)

Using a method similar to the preparation of compound NTC001, 4-trifluoromethylphenylhydrazine was replaced with 4-cyanophenylhydrazine hydrochloride, and finally purified by column chromatography to obtain compound NTC021 with a yield of 11%: ¹ HNMR (300MHz , DMSO-d ₆ ): δ11.53 (brs, 1H), 7.93 (s, 1H), 7.48 (d, J=8.4Hz, 1H), 7.39 (d, J=8.4Hz, 1H), 7.31-7.23 (m, 5H), 4.73 (s, 2H), 3.87-3.83 (m, 4H), 2.73-2.63 (m, 2H).

Synthesis of Example 1-22, 6-nitro-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC022)

Using a method similar to the preparation of compound NTC001, 4-trifluoromethylphenylhydrazine was replaced by 4-nitrophenylhydrazine hydrochloride, and finally purified by column chromatography to obtain compound NTC022 with a yield of 6%: ¹ HNMR (300MHz , DMSO-d ₆ ): δ11.70 (brs, 1H), 8.40 (d, J=9.0Hz, 1H), 7.98-7.94 (m, 1H), 7.48 (d, J=9.0Hz, 1H), 7.32 -7.24 (m, 5H), 4.74 (s, 2H), 3.88-3.85 (m, 4H), 2.73-2.69 (m, 2H).

Synthesis of Example 1-23, 6-benzyloxy-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC023)

Take 5-hydroxytryptamine hydrochloride as raw material, first protect the hydroxyl group with benzyl group, then similar to Example 1-1, and finally obtain the compound NTC023 after purification by column chromatography, the yield is 20%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ10.69 (brs, 1H), 7.52-7.18 (m, 11H), 7.01-6.97 (m, 1H), 6.77-7.73 (m, 1H), 5.06 (s, 2H), 4.68 (s, 2H), 3.85-3.79 (m, 4H), 2.66-2.53 (m, 2H).

Synthesis of Example 1-24, 6-(methoxycarbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC024)

Using a method similar to that of Example 1-1, replace 4-trifluoromethylphenylhydrazine hydrochloride with 4-carboxyphenylhydrazine hydrochloride to obtain 5-carboxytryptamine and then protect the carboxyl group with methyl ester before proceeding to follow-up After the reaction, the compound NTC024 was finally purified by column chromatography with a yield of 35%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ11.32 (brs, 1H), 8.10-8.06 (m, 1H), 7.71-7.67 (m, 1H), 7.40-7.22 (m, 6H), 4.73 (s, 2H), 3.87-3.83 (m, 7H), 2.73-2.63 (m, 2H).

Synthesis of Example 1-25, 6-amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC025)

Using hydrogen as a reducing agent and palladium carbon as a catalyst to reduce NTC022, the compound NTC025 was obtained after purification by column chromatography with a yield of 67%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ10.41 (brs, 1H), 7.35-7.25(m, 7H), 7.02(d, J=8.4Hz, 1H), 6.59-6.54(m, 1H), 6.46(d, J=8.4Hz, 1H), 4.67(s, 2H), 3.89 -3.82 (m, 4H), 2.60-2.54 (m, 2H).

Synthesis of Example 1-26, 6-hydroxyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC026)

Using a method similar to the preparation of compound NTC025, compound NTC026 was obtained after purification by column chromatography with a yield of 85%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ10.50 (brs, 1H), 8.59-5.56 (m , 1H), 7.34-7.23(m, 5H), 7.07(d, J=8.7Hz, 1H), 6.68-6.64(m, 1H), 6.53(d, J=8.7Hz, 1H), 4.65(s, 2H), 3.85-3.79 (m, 4H), 2.58-2.51 (m, 2H).

Synthesis of Example 1-27, 6-carboxy-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC027)

NTC024 was hydrolyzed at room temperature in methanol-water mixed solution of inorganic alkali lithium hydroxide to obtain product NTC027 with 100% yield: ¹ HNMR (300MHz, DMSO-d ₆ ): δ12.35(brs, 1H), 11.26(brs, 1H), 8.22(s, 1H), 7.64-7.61(m, 1H), 7.34-7.25(m, 6H), 3.96(s, 2H), 3.75-3.74(m, 2H), 3.38-3.35(m, 2H), 2.82-2.78 (m, 2H). Synthesis of Example 1-28, 6-methyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC028)

3-(2,3-piperidinedione)-(4-(methoxycarbonyl)phenyl)-hydrazone (505mg, 1.93mmol, preparation method reference Syn.Comm.2007, 37, 1273-1280) Dissolve in 20ml of formic acid, stir at 80°C for 24 hours, remove the formic acid under reduced pressure, and obtain off-white solid 1-oxo-6-(methoxycarbonyl)-1,3,4,9-tetrahydro-β after conventional treatment -carboline, yield 55%. The carboline intermediate was reduced by lithium aluminum hydride and then coupled with phenylacetic acid to obtain the final product NTC028 with a yield of 26%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ10.71(brs, 1H), 7.34-7.13( m, 7H), 6.85 (d, J = 8.1 Hz, 1H), 4.68 (s, 2H), 3.85-3.80 (m, 4H), 2.64-2.55 (m, 2H), 2.34 (s, 3H).

Synthesis of Example 1-29, 5-amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC029)

Using a method similar to the preparation of compound NTC001, 4-nitrophenylhydrazine is replaced by trifluoromethylphenylhydrazine, and the target compound 5-nitro-N-phenylacetyl-1,3,4,9 can be obtained by preparing the liquid phase -tetrahydro-1H-β-carboline and 7-nitro-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline.

Take the intermediate 5-nitro-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (235mg, 0.7mmol) in a 25ml round bottom flask, add 1ml DMF to dissolve, and then Add 4ml of methanol for dilution, add 0.5% (weight ratio) of Pd/C under nitrogen atmosphere, and continue to feed hydrogen for 2h, TLC shows that the substrate disappears. The solvent was distilled off, and the target compound 5-amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (159 mg. Yield: 74%) was obtained after purification by column chromatography. ¹ HNMR (DMSO, 300MHz): δ10.52(brs, 1H), 7.34-7.21(m, 5H), 6.69(dd, J=7.5Hz, 7.8Hz, 1H), 6.53(d, J=8.1Hz, 1H), 6.13(d, J=7.5Hz, 1H), 4.72(brs, 2H), 4.62(s, 2H), 3.84-3.78(m, 4H), 2.92(t, J=7.1Hz, 2H).

Example 1-30 Synthesis of 7-amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC030)

Using a method similar to the preparation of compound NTC001, 7-nitro-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline was used instead of 5-nitro-N-phenylacetyl- 1,3,4,9-tetrahydro-1H-β-carboline, purified by column chromatography to obtain 7-amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β- Carboline (46 mg. Yield: 29%). ¹ H NMR (DMSO, 300MHz): δ10.20 (brs, 1H), 7.31-7.18 (m, 5H), 6.96 (dd, J=8.4Hz, 1H), 6.45 (d, 1H), 6.30 (d, J =8.4Hz, 1H), 4.60(brs, 2H), 4.56(s, 2H), 3.81-3.74(m, 4H), 3.30(t, J=5.7Hz, 2H).

Embodiment 1-31 Synthesis of 5-(2-(N-morpholinyl)) acetylamino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC031)

The intermediate 5-amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (50 mg, 0.16 mmol) and chloroacetyl chloride (19 μl, 0.24 mmol) were added at 0°C In the solution of triethylamine and DMF, after stirring for 2 hours, morpholine (30 μl, 0.32 mmol) was added dropwise and stirred for 5 hours. TLC detected that the starting material disappeared. The reaction solution was added to ice water, and a white solid was precipitated, which was the product (43 mg, yield 62.3%). ¹ HNMR (DMSO, 300MHz): δ10.99(brs, 1H), 9.46(brs, 1H), 7.53(d, J=6.9Hz, 1H), 7.28-7.23(m, 5H), 7.08-7.06(m , 1H), 6.97-6.93(m, 1H), 4.69(s, 2H), 3.86(s, 4H), 3.62(s, 4H), 3.10(s, 2H), 2.87(s, 2H), 2.54( s, 4H).

Example 1-325-(2-(4-methylpiperazinyl))acetylamino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC032) synthesis

Using the same method as in Example 1-31, replacing morpholine with N-methylpiperazine, the product NTC032 (33 mg, yield 57%) was obtained. ¹ H NMR (DMSO, 300MHz): δ10.98 (brs, 1H), 9.55 (brs, 1H), 7.59 (d, J = 7.8Hz, 1H), 7.28-7.21 (m, 5H), 7.03 (d, J =7.8Hz, 1H), 6.94(dd, J=7.8Hz, 7.8Hz, 1H), 4.68(s, 2H), 3.84(s, 4H), 3.06(s, 2H), 2.91(s, 2H), 2.46(s, 4H), 2.35(s, 4H), 2.16(s, 3H).

Example 1-33 Synthesis of 5-(2-amino)acetylamino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC033)

5-Amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (50 mg, 0.16 mmol) and Boc-L-glycine (42 mg, 0.24 mmol) were dissolved in DMF ( 3ml), EDCHCl (60mg, 0.31mol) and HOBt (36mg, 0.26mmol) were added at 0°C, and reacted at room temperature for 4 hours. After TLC detected that the raw materials disappeared, the reaction solution was added to water, extracted with ethyl acetate, and washed with water. , washed with salt, and purified by silica gel column to obtain 137 mg of intermediate. The above-mentioned intermediate was dissolved in dichloromethane, a solution of hydrogen chloride in 1,4-dioxane was added, and the reaction was stirred overnight at room temperature. After the reaction was complete, it was washed with water, saturated sodium carbonate, salt, and vacuum-dried to obtain the target compound (32 mg, yield 55%). ¹ HNMR (DMSO, 300MHz): δ10.95 (brs, 1H), 7.56 (d, J=7.5Hz, 1H), 7.30-7.22 (m, 5H), 7.05 (d, J=7.8Hz, 1H), 6.94 (dd, J = 7.5Hz, 7.8Hz, 1H), 4.68 (s, 2H), 3.84-3.82 (m, 4H), 3.25 (s, 2H), 2.95 (s, 2H).

Example 1-34 Synthesis of 5-(2-threonine base) amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC034)

Using the same method as in Example 1-33, Boc-L-glycine was replaced by Boc-L-threonine to obtain the target compound (22 mg, yield 69%). ¹ HNMR (DMSO, 300MHz): δ10.95(brs, 1H), 9.83(brs, 1H), 7.66-7.58(m, 1H), 7.28-7.23(m, 5H), 7.08-7.03(m, 1H) , 6.98-6.93(m, 1H), 4.69(s, 2H), 4.14-4.01(m, 1H), 3.94-3.83(m, 5H), 3.51-3.48(m, 1H), 3.01-2.96(m, 2H), 1.40-1.34 (m, 2H), 1.19-1.14 (m, 3H).

Example 1-35 5-(2-proline base) amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC035) synthesis

Using the same method as in Example 1-33, Boc-L-glycine was replaced by Boc-L-proline to obtain the target compound (23 mg, yield 72%). ¹ HNMR (DMSO, 300MHz): δ10.96(brs, 1H), 10.22(brs, 1H), 7.73-7.62(m, 1H), 7.28-7.20(m, 5H), 7.03-7.01(m, 1H) , 6.98-6.90(m, 1H), 4.70(s, 2H), 3.93-3.70(m, 5H), 3.97-3.73(m, 4H), 2.08-2.02(m, 1H), 1.85-1.67(m, 2H), 1.67-1.61 (m, 2H).

Synthesis of Example 1-36, 9-(4-bromobenzyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC036)

Take compound 1,3,4,9-tetrahydro-1H-β-carboline (225 mg) in dichloromethane, add EDC (326 mg) and HOBt (194 mg) under an argon atmosphere, and stir under ice bath for 15 Minutes later, phenylacetic acid (218mg) was added, and the compound was stirred and reacted at room temperature for 5-8 hours. The reaction solution was poured into an ice bath, extracted twice with ethyl acetate, and the organic phase was washed with water and saturated brine. Dry over sodium sulfate and concentrate under reduced pressure to obtain a crude product. After purification by column chromatography, 336 mg of N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline was obtained with a yield of 89%. The intermediate was reacted with p-bromobenzyl bromide under the action of NaH in DMF for 1 hour to obtain NTC036 with a yield of 50%: ¹ HNMR (300MHz, DMSO): δ7.50-7.44 (m, 4H), 7.29-7.25 (m, 4H), 7.24-6.96 (m, 5H), 5.36 (s, 2H), 4.70-4.67 (m, 2H), 3.86-3.76 (m, 4H), 2.71-2.65 (m, 2H).

Example 1-37, 9-methyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (synthesis of NCT037)

N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline was reacted with p-iodomethane in DMF under the action of NaH at 0°C for 1 hour to obtain NTC037 with a yield of 80%: ¹ HNMR (DMSO, 300MHz): δ7.36-7.29(m, 2H), 7.25-7.20(m, 5H), 7.05-7.00(m, 1H), 7.95-6.89(m, 1H), 4.69(s, 2H ), 3.81(s, 2H), 3.75-3.71(t, J=5.7Hz, 2H), 3.56(s, 3H), 3.26(t, J=5.7Hz, 2H).

Synthesis of Example 1-38, 8-fluoro-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC038)

Using a method similar to the preparation of compound NTC001, 4-trifluoromethylphenylhydrazine was replaced by o-fluorophenylhydrazine, and finally compound NTC038 was obtained after purification by column chromatography, with a yield of 56%: ¹ HNMR (DMSO, 300MHz): δ11 .29(brs, 1H), 7.24-7.15(m, 6H), 6.88-6.81(m, 2H), 4.67(s, 2H), 3.81-3.77(m, 4H), 2.93(s, 2H), 2.88 -2.61 (m, 2H).

Example 1-39, Synthesis of 6-(2-amino)acetylamino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC039)

Using the same method as in Example 1-33, replace 5-amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline with 6-amino-N-phenylacetyl -1,3,4,9-tetrahydro-1H-β-carboline yielded the target compound NTC039 in 40% yield: ¹ HNMR (DMSO, 300MHz): δ10.79 (brs, 1H), 7.75-7.73 (m , 1H), 7.35-7.16 (m, 8H), 4.69 (s, 2H), 3.86-3.80 (m, 4H), 3.24 (s, 2H), 2.64-2.55 (m, 2H).

Example 1-40, Synthesis of N-phenylacetyl-6,8-difluoro-1,3,4,9-tetrahydro-1H-β-carboline (NTC040)

Using a method similar to the preparation of compound NTC001, 4-trifluoromethylphenylhydrazine was replaced by 2,4-difluorophenylhydrazine, and finally purified by column chromatography to obtain compound NTC040 with a yield of 10%: ¹ HNMR (DMSO, 300MHz): δ11.45(brs, 1H), 7.34-7.20(m, 5H), 7.06-7.02(m, 1H), 6.94-6.86(m, 1H), 4.71(s, 2H), 3.86-3.80( m, 4H), 2.65-2.55 (m, 2H).

Example 1-41, Synthesis of N-phenylacetyl-6,8-difluoro-9-p-bromobenzyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC041)

Take N-phenylacetyl-6,8-difluoro-9-p-bromobenzyl-1,3,4,9-tetrahydro-1H-β-carboline and p-bromobenzyl bromide in DMF under the action of NaH Reaction at 0°C for 1 hour yielded NTC041 with a yield of 46%: ¹ HNMR (DMSO, 300MHz): δ7.52-7.50 (m, 2H), 7.32-7.11 (m, 6H), 6.97-6.89 (m, 3H) , 5.40 (s, 2H), 4.72 (s, 2H), 3.86-3.78 (m, 4H), 2.67-2.62 (m, 2H).

Synthesis of Example 1-42, 9-benzyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC042)

Using a method similar to the preparation of compound NTC037, iodomethane was replaced by benzyl bromide, and finally purified by column chromatography to obtain compound NTC042 with a yield of 58%: ¹ HNMR (300MHz, DMSO): δ7.43-7.41 (m, 2H ), 7.31-7.23(m, 8H), 7.08-7.03(m, 4H), 5.37(s, 2H), 4.72-4.69(m, 2H), 3.86-3.75(m, 4H), 2.71-2.65(m , 2H).

Synthesis of Example 1-43, 9-(4-fluorobenzyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC043)

Using a method similar to the preparation of compound NTC037, iodomethane was replaced by p-fluorobenzyl bromide, and finally purified by column chromatography to obtain compound NTC043 with a yield of 72%: ¹ HNMR (300MHz, DMSO): δ7.44-7.41 (m , 2H), 7.31-7.21(m, 5H), 7.17-7.01(m, 6H), 5.36(s, 2H), 4.71-4.68(m, 2H), 3.86-3.77(m, 4H), 2.73-2.65 (m, 2H).

Synthesis of Example 1-44, 9-(4-methyl formate benzyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC044)

Using a method similar to the preparation of compound NTC037, iodomethane was replaced by methyl 4-bromomethylbenzoate, and finally purified by column chromatography to obtain compound NTC044 with a yield of 79%: ¹ HNMR (300MHz, DMSO): δ7. 90-7.87(m, 2H), 7.45-7.31(m, 3H), 7.29-7.14(m, 9H), 5.47(s, 2H), 4.69-4.65(m, 2H), 4.28(m, 3H), 3.86-3.74 (m, 4H), 2.67-2.53 (m, 2H).

Synthesis of Example 1-45, 9-(4-carboxybenzyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC045)

Take NTC044 and heat it in 1N NaOH aqueous solution for 1 hour, cool to adjust the pH to 1, extract with EtOAc, and distill under reduced pressure to obtain NTC045 with a yield of 99%: ¹ HNMR (300MHz, DMSO): δ12.90(s, 1H )7.87-7.84(m, 2H), 7.45-7.39(m, 3H), 7.32-7.24(m, 4H), 7.20-7.06(m, 4H), 5.48(s, 2H), 4.71-4.66(m, 2H ), 3.86-3.75 (m, 4H), 2.67-2.64 (m, 2H).

Synthesis of Example 1-46, 9-(methoxycarbonylmethyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC046)

Using a method similar to the preparation of compound NTC037, iodomethane was replaced by methyl bromoacetate, and finally purified by column chromatography to obtain compound NTC046 with a yield of 75%: ¹ HNMR (300MHz, DMSO): δ7.42-7.23 (m , 7H), 7.10-7.02(m, 2H), 5.09(s, 2H), 4.76-4.67(m, 2H), 3.88-3.80(m, 4H), 3.68(s, 3H), 2.69-2.60(m , 2H).

Synthesis of Example 1-47, 9-(carbonylmethyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC047)

Take NTC046 and heat it in 1N NaOH aqueous solution for 1 hour, cool to adjust the pH to 1, extract with EtOAc, and distill under reduced pressure to obtain NTC047 with a yield of 99%: ¹ HNMR (300MHz, DMSO): δ12.95(s, 1H ( m, 2H).

Example 1-48, Synthesis of 9-(4-(morpholino)carbonylmethyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC048)

Take NTC047, EDCHCl, and HOBt and stir in DMF for 10 minutes, then add morpholine dropwise and react at room temperature for 3 hours, extract and purify to obtain NCT048 with a yield of 89%: ¹ HNMR (300MHz, DMSO): δ7.39-7.23 (m, 7H), 7.10-6.99(m2H), 5.13(s, 2H), 4.66-4.62(m, 2H), 3.88-3.79(m, 4H), 3.70-3.68(m, 2H), 3.63-3.59 (m, 4H), 3.45-3.44 (m, 2H), 2.69-2.60 (m, 2H).

Synthesis of Example 1-49, 5-methoxycarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NCT049)

Using a method similar to the preparation of compound NTC001, 4-trifluoromethylphenylhydrazine was replaced by 3-hydrazinobenzoic acid methyl ester, and the liquid phase was prepared to obtain 5-(methoxycarbonyl)-N-phenylacetyl -1,3,4,9-Tetrahydro-1H-β-carboline NCT049, yield 16%: ¹ HNMR (DMSO, 300MHz): δ11.33 (brs, 1H), 7.96 (d, J=7.5Hz , 7.8Hz, 1H), 7.61(d, J=7.5Hz, 1H), 7.47(dd, J=7.5Hz, 1H), 7.34-7.24(m, 5H), 4.76(s, 2H), 3.87-3.84 (m, 7H), 2.63 (d, 2H).

Synthesis of Example 1-50, 5-(Valine amino)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NCT050)

Using the same method as in Example 1-33, Boc-L-glycine was replaced by Boc-L-valine to obtain the target compound (22mg, yield 55%): ¹ HNMR (DMSO, 300MHz): δ10.99( brs, 1H), 9.73(s, 1H), 7.53(d, J=7.5Hz, 1H), 7.27-7.22(m, 5H), 7.04(d, J=7.8Hz, 1H), 6.94(dd, J =7.5Hz, 7.8Hz, 1H), 4.69(s, 2H), 3.84-3.81(m, 4H), 2.93(s, 1H), 2.77(s, 2H), 2.28(s, 1H), 0.97-0.87 (m, 6H).

Synthesis of Example 1-51, 5-(alanine amino)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NCT051)

Using the same method as in Example 1-33, Boc-L-glycine was replaced by Boc-L-alanine to obtain the target compound (27mg, yield 53%): ¹ HNMR (DMSO, 300MHz): δ10.89( brs, 1H), 9.70(s, 1H), 7.84(d, J=7.5Hz, 1H), 7.25-7.21(m, 5H), 7.19(d, J=7.8Hz, 1H), 7.02(dd, J =7.5Hz, 7.8Hz, 1H), 5.11(brs, 2H), 4.63(s, 2H), 3.83-3.81(m, 4H), 3.74(s, 1H), 2.99(s, 2H), 1.28(d , 3H).

Example 1-52, Synthesis of 5-(3-amino)propionylamino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NCT052)

Using the same method as in Example 1-33, Boc-L-glycine was replaced by Boc-L-β-alanine to obtain the target compound (35 mg, yield 45%): ¹ HNMR (DMSO, 300 MHz): δ10. 87(brs, 1H), 9.69(s, 1H), 7.84(d, J=7.5Hz, 1H), 7.24-7.20(m, 5H), 7.18(d, J=7.8Hz, 1H), 7.02(dd , J=7.5Hz, 7.8Hz, 1H), 5.11(brs, 2H), 4.48(s, 2H), 3.85-3.81(m, 4H), 3.03(t, J=5.4Hz, 2H), 2.99(s , 2H), 1.28 (t, J=5.4Hz, 2H).

Claims (10)

1. aromatic base alkyloyl tetrahydro-beta-carboline and derivative thereof or a pharmacy acceptable salt, is characterized in that, represented by following structural formula (VII):

Wherein: X is CO or NH;

be selected from phenyl;

R ₁for the substituting group on aromatic nucleus, be selected from hydrogen;

R ₆be selected from hydrogen;

R ₁₂be selected from any one in following groups: amino-acid residue, wherein, described amino-acid residue is selected from glycine, L-Ala, α-amino-isovaleric acid, Isoleucine, leucine, tyrosine, phenylalanine, Histidine, proline(Pro).

2. aromatic base alkyloyl tetrahydro-beta-carboline class according to claim 1 and derivative thereof or a pharmacy acceptable salt, is characterized in that, comprises the acid salt that described acyl group tetrahydro-beta-carboline micromolecular organic compound is formed with acid; Wherein, described acid comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, tartrate, Whitfield's ointment, citric acid, methylsulfonic acid, tosic acid, lactic acid, pyruvic acid, toxilic acid or succsinic acid.

3. aromatic base alkyloyl tetrahydro-beta-carboline according to claim 1 and 2 and derivative thereof or pharmacy acceptable salt, it is characterized in that, it is with radioactivity, fluorophor or biotin labeling.

4. aromatic base alkyloyl tetrahydro-beta-carboline according to claim 1 and 2 and derivative thereof or pharmacy acceptable salt, is characterized in that, comprising:

6-(L-Ala carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline

6-(proline(Pro) carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline

6-(glycine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline

6-(tyrosine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline

6-(Histidine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline

5-(2-is amino) acetylamino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline

5-(2-proline(Pro) base) amino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline

6-(2-is amino) acetylamino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline

5-(α-amino-isovaleric acid is amino)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline

5-(L-Ala is amino)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline.

5. a pharmaceutical composition, wherein containing aromatic base alkyloyl tetrahydro-beta-carboline according to claim 1 and derivative thereof or pharmacy acceptable salt, and pharmaceutically acceptable carrier.

6. pharmaceutical composition according to claim 5, is characterized in that, described pharmaceutical composition is formulated into injectable fluid, aerosol, emulsifiable paste, gelifying agent, pill, capsule, syrup, transdermal patch.

7. aromatic base alkyloyl tetrahydro-beta-carboline according to claim 1 and derivative thereof or the pharmacy acceptable salt application in the medicine of preparation treatment malignant tumour; Wherein, described malignant tumour comprises head and neck cancer, thyroid carcinoma, the esophageal carcinoma, nasopharyngeal carcinoma, liver cancer, lung cancer, prostate cancer, skin carcinoma, osteocarcinoma, cervical cancer, intestinal cancer, carcinoma of the pancreas, mammary cancer, leukemia, ovarian cancer, cancer of the stomach, bladder cancer, kidney, skin carcinoma, oral carcinoma and malignant lymphoma.

8. aromatic base alkyloyl tetrahydro-beta-carboline according to claim 1 and derivative thereof or the pharmacy acceptable salt application in the medicine of preparation treatment Malignant tumor of bonal metastasis and recurrence; Wherein, described malignant tumour comprises head and neck cancer, thyroid carcinoma, the esophageal carcinoma, nasopharyngeal carcinoma, liver cancer, lung cancer, prostate cancer, skin carcinoma, osteocarcinoma, cervical cancer, intestinal cancer, carcinoma of the pancreas, mammary cancer, leukemia, ovarian cancer, cancer of the stomach, bladder cancer, kidney, skin carcinoma, oral carcinoma, malignant lymphoma.

9. aromatic base alkyloyl tetrahydro-beta-carboline according to claim 1 and derivative thereof or the pharmacy acceptable salt application in the medicine of preparation treatment lung cancer and prostate cancer.

10. the application according to any one of claim 7-9, is characterized in that, described medicine be used alone or with other drug conbined usage.